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Subjects

Abstract

The mammalian gut is colonized by numerous microorganisms collectively termed the microbiota, which have a mutually beneficial relationship with their host1,2,3. Normally, the gut microbiota matures during ontogeny to a state of balanced commensalism marked by the absence of adverse inflammation4,5. Subsets of innate lymphoid cells (ILCs) and conventional T cells are considered to have redundant functions in containment and clearance of microbial pathogens6,7, but how these two major lymphoid-cell populations each contribute to shaping the mature commensal microbiome and help to maintain tissue homeostasis has not been determined. Here we identify, using advanced multiplex quantitative imaging methods, an extensive and persistent phosphorylated-STAT3 signature in group 3 ILCs and intestinal epithelial cells that is induced by interleukin (IL)-23 and IL-22 in mice that lack CD4+ T cells. By contrast, in immune-competent mice, phosphorylated-STAT3 activation is induced only transiently by microbial colonization at weaning. This early signature is extinguished as CD4+ T cell immunity develops in response to the expanding commensal burden. Physiologically, the persistent IL-22 production from group 3 ILCs that occurs in the absence of adaptive CD4+ T-cell activity results in impaired host lipid metabolism by decreasing lipid transporter expression in the small bowel. These findings provide new insights into how innate and adaptive lymphocytes operate sequentially and in distinct ways during normal development to establish steady-state commensalism and tissue metabolic homeostasis.

Acknowledgements

We thank Y. Choi and D.M. Kobuley for providing germ free Rag1−/− mice and performing SFB mono-colonization; M. Oukka and S. K. Durum for providing mice; M. Mack, B. Gao and Y. Umesaki for providing anti-CCR2 antibody, IL-22 adenovirus and SFB faecal pellets; C. Eigsti, V. Nair and J. Davis for cell sorting, scanning electron microscopy and microbiota analysis; J. Zhu for discussions; and members of the Laboratory of Systems Biology for their comments during the course of these studies and input during preparation of this manuscript. Y.H. was supported by an NIAID K99 award (1K99AI123350-01A1). This research was supported by the Intramural Research Program of NIAID, NIH.

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Contributions

K.M. designed and conducted most of the experiments and data analysis and prepared the manuscript; A.P.B., S.T. and Y.H. helped with cell isolation and transfer; L.Z. measured mouse body composition; N.B. performed the analysis of microbiota translocation; A.J.M. performed the RNA-seq and data analysis; M.Y.G. provided helpful suggestions regarding imaging and histo-cytometry; Y.B. provided helpful suggestions, discussed data interpretation and contributed to the manuscript; and R.N.G. designed experiments, interpreted data and helped to write the manuscript.

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Editorial Summary

How innate and adaptive immunity shapes the microbiota

Mammalian intestines are colonized by trillions of bacteria that help to maintain immunologic and metabolic health under homeostatic conditions, but that can induce effector T cell responses and inflammation under adverse conditions. Ronald Germain and colleagues use histocytochemistry to investigate the role of two major lymphoid-cell populations in the maintenance of immune homeostasis in the small intestine. They show that effector T helper 17 cells regulate the number of bacteria present in the small intestine, whereas regulatory T cells suppress the induction of the pro-inflammatory cytokine IL-23 by CCR2+ monocytes in response to stimuli from commensal bacteria. This process leads to downregulation of IL-22 production by group 3 innate lymphoid cells (ILC3s) and subsequent activation of intestinal epithelial cells. In the absence of this adaptive immune effect, ILC3s remain constitutively activated after weaning, and the persistent production of IL-22 results in inflammation and abnormal lipid metabolism.